Myeloid leukemia is a hematologic malignancy characterized by the block in differentiation and abnormal proliferation of clonal myeloid blast cells. Despite extensive clinical research with numerous combinations of cytotoxic agents the overall prognosis of myeloid leukemia patients remains poor, thus hunt for better effective agents is ongoing (U. Krug, et. al.; Curr Opin Hematol, 2010, 17(2):85-90; W. W. Ma, et. al.; Cancer J Clin, 2009, 59(2), 111-37). Ormeloxifene (3,4-trans-2,2-dimethyl-3-phenyl-4-p-(beta-pyrrolidinoethoxy)phenyl-7-methoxychroman), also known as Centchroman, the chemical structure of which is shown in FIG. 1a, is a potent non-steroidal selective estrogen receptor modulator (SERM) used as oral contraceptive for birth control. ORM suppresses the receptors in the reproductive organs like the ovaries, uterus and breasts while it stimulates the estrogen receptors of organs like the bones (A. Mukhopadhyay et. al.; Cancer Lett, 1999, 144(2),137-43; M. M. Singh, Med Res Rev, 2001, 1(4), 302-47; V Kumar et. al.; Contraception, 2006, 74(2), 165-73).
Substantial evidence has been amassed to support the premise that ORM has potential anticancer activity (N. C. Misra et. al.; Int J Cancer, 1989, 43(5), 781-3). So, while it acts as a birth control pill it can prevent breast cancers, uterine cancers and stimulate the formation of new bones (M. M. Singh, Med Res Rev, 2001,21 (4):302-347). In a published study, Mishra et. al, evaluated the role of ORM in breast cancer patients. Apparently, treatment with ORM was evaluated in 4 male and 75 female patients with advanced breast cancer. The overall response rates including both male and female cases, was 40.5%. Among the female patients, the overall response rate was 38.7%. One of the 4 male patients showed a complete response and 2 showed partial responses. The responses were more marked for bone, pulmonary, soft tissue, skin and lymph-node metastases than for liver metastases (N. C. Misra, et. al.; Int J Cancer, 1989, 43(5), 781-3). Furthermore, ORM can reduce the mutagenic effects of known genotoxic compounds dimethylbenz[a]anthracene (DMBA), cyclophosphamide (CP), mitomycin C (MMC) and ethyl methanesulfonate (EMS) in Salmonella. These protective activities of ORM against the known positive mutagens in the Salmonella may be due to induction of apoptosis by ORM, which leads to the elimination of cells damaged by these mutagens from the cell population (A. K. Giri, et. al.; Mutagenesis, 1999, 14 (6):613-620). Arrested differentiation and increased cell proliferation due to transformation of immature hematopoietic cells is the hallmark of leukemia. This prolongs the growth factor-independent survival of leukemic progenitors by inhibiting the apoptosis. Therefore, agents that can eliminate transformed cells by induction of apoptosis and differentiation in arrested cells rather than merely slowing down their proliferation may have larger therapeutic potential. The increased understanding of apoptosis pathways has directed attention to components of these pathways as potential targets for therapeutic agents (D. G. Tenen, Nat Rev Cancer, 2003, 3(2):89-101). Indeed, an increasing number of previously identified therapeutic agents including, retinoids, vitamin D3 analogues, Benzothipopenes, Chlorogenic acid, Guggulsterone, Shikonin, Boswelic Acid, CDDO, Resveratrol and others were found to enhance apoptosis and induce differentiation in a variety of premalignant or malignant leukemia cell types in vitro and in a few animal models in vivo (G. Bandyopadhyay et. al.; Blood, 2004, 104 (8):2514-2522; Z. Estrov et. al.; Blood, 2003, 102(3):987-995; Y. Jing, et. al.; Cancer Res, 2005, 65(17) 7847-7855; X. Mao et. al.; Cell Res 2008, 18(8):879-888; L. Xia et. al.; Mol Cancer Ther, 2005, 4(3):381-388). With this pre-context, in our earlier study we have showed the anticancer activity of ormeloxifene in myeloid leukemia cells. We have shown that ormeloxifene at an IC50 of 7.5 uM induces apoptosis in HL60, U937 and K562 cells (P. Pal, et. al; Proteomics, 2011, 11 (8):1517-1529). Our studies clearly demonstrate that ormeloxifene can induce apoptosis in myeloid leukemia cells. Most of the anticancer compounds having potential to induce apoptosis in leukemic cells have been shown to induce differentiation at subapoptotic doses (S. Koschmieder, et. al.; Blood, 2007, 110 (10):3695-3705). Therefore, here we sought to investigate if ORM has also any differentiation inducing potential in myeloid leukemia cells and thus in the present invention we have investigated the new role of non-steroidal anti contraceptive “Ormeloxifene” in myeloid leukemia.
Earlier P Pal et al reported that this antileukemic agent ORM induces apoptosis (P. Pal et al.; Proteomics, 2011, 11 (8):1517-1529) at a concentration of 7.5 uM. However results of present invention reveals that ORM at a concentration of 7.5 uM also induces differentiation when used for a shorter time period. Moreover ORM at a concentration of 1.0 uM also induces differentiation when treated for longer time period in myeloid leukemia cells. Therefore ORM is advantageous over other antileukemic agents which either induce apoptosis or differentiation alone. This antileukemic agent induces myeloid differentiation which is marked by induction of myeloid differentiation markers.